The purpose of this project is to investigate the regulation of fatty acid utilization in heart muscle. The isolated perfused rat heart will be used for these studies. This preparation utilized FFA in preference to carbohydrate as substrate for energy metabolism. The rate of fatty acid utilization can be varied by raising the concentration of exogenous fatty acid, by increasing cardiac work and by decreasing oxidative metabolism. The mechanisms of these changes in fatty acid utilization will be investigated in the whole tissue by measuring the rates of fatty acid uptake and oxidation and the levels of key metabolic intermediates in the pathways. Earlier studies using this approach have indicated that the rate of the citric acid cycle controls the rate of fatty acid oxidation at physiological concentrations of palmitate and at low cardiac work loads. With increased cardiac work, the cycle was accelerated and oxidation of fatty acyl carnitine limited utilization of fatty acids. The mechanisms of these effects will be investigated in the whole tissue and in isolated mitochondria. Increased cardiac work also accelerated utilization of tissue lipids in hearts that were perfused with buffer containing either no substrate, glucose or glucose plus acetate but not when palmitate was present. Esterification of FFA to triglycerides increased with increased concentration of FFA and with decreased oxidative metabolism. The mechanisms of these effects of substrate, cardiac work and oxidative metabolism on lipolysis will be investigated in the whole tissue and in broken cell preparations.